P2X7 is a ligand-gated ion channel that responds to elevated ATP levels, commonly found at sites of injury and inflammation, by mediating the cellular efflux of K+ and the influx of Ca++ and Nat P2X7 is expressed by leukocytes, in particular by T cells, B cells, neutrophils and monocytes/macrophages, and by chondrocytes, synoviocytes, microglia and astrocytes. The major downstream effector function of P2X7 activation is the processing and release of mature forms of the proinflammatory cytokines IL-1β and IL-18 which involves the activation of caspase-1 (ICE). This occurs through the action of NALP3/cryopyrin-dependent inflammasomes. Activation of P2X7 also has been shown to increase levels of other mediators of inflammation including MMPs, PGE2 and TNF-α, although the mechanisms for these effects are not as well studied. There are data supporting a role for P2X7 in signaling cascades such as NF-κB and these pathways might provide a link to non-inflammasome-based mediator production. Current knowledge of P2X7 inhibitors indicates that antagonism of P2X7 in vivo reduces inflammatory cytokines and inflammation and reduces both inflammatory hyperalgesia and neuropathic pain.
Rheumatoid arthritis is another disease linked to the activity of P2X7. Rheumatoid arthritis is characterized by significant synovial inflammation and destruction of extracellular matrix and articular structures including cartilage and bone. Cytokine pathways, including TNF-α, IL-1β, IL-18 and IL-6, are thought to play significant roles in this process. This has been clinically validated for TNF-α and IL-6. Inflamed syriovium contains a variety of cells, including macrophage, T cells, B cells, synoviocytes, fibroblasts and chondrocytes which are known to express P2X7 and contribute to the production of these cytokines. Therefore, P2X7 antagonists are potentially useful as they may inhibit the inflammatory cascade observed in rheumatoid arthritis.
The expression of P2X7 on immune cells and its role in cytokine production also suggest the potential utility of P2X7 antagonists in the treatment of chronic obstructive pulmonary disease (COPD), asthma and inflammatory bowel disease (IBD). P2X7-expressing cells including macrophage, T cells and neutrophils through their mediators such as IL-18 and proteases play important roles in the cascade of events leading to lung tissue destruction and reduced lung function in COPD patients. Similarly, macrophage and T cells and their mediators play important roles in the path physiology of asthma and IBD.
There remains a need in the art for novel compounds which are useful for treating inflammatory diseases and pain. This invention addresses that need.